Prominent Non-Memory Deficits in Alzheimer’s Disease Are Associated with Faster Disease Progression

Article type: Research Article

Authors: Scheltens, Nienke M.E.^{a; *} | Tijms, Betty M.^a | Heymans, Martijn W.^b | Rabinovici, Gil D.^c | Cohn-Sheehy, Brendan I.^c | Miller, Bruce L.^c | Kramer, Joel H.^c | Wolfsgruber, Steffen^d | Wagner, Michael^d | Kornhuber, Johannes^e | Peters, Oliver^f | Scheltens, Philip^a | van der Flier, Wiesje M.^{a; b} | Amsterdam Dementia Cohort, Alzheimer’s Disease Neuroimaging Initiative, German Dementia Competence Network, University of San Francisco Memory and Aging Center¹

Affiliations: [a] Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands | [b] Department of Epidemiology and Biostatistics, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, The Netherlands | [c] Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, USA | [d] Department of Psychiatry, University of Bonn, Bonn, Germany, and German Center for Neurodegenerative Diseases, Bonn, Germany | [e] Department of Psychiatry, Friedrich-Alexander-University Erlangen, Erlangen, Germany | [f] Department of Psychiatry, Charité Berlin, Campus Benjamin Franklin, Berlin, Germany

Correspondence: [*] Correspondence to: Nienke M.E. Scheltens, MD, Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Tel.: +31 20 4448523; Fax: +31 20 444 0397; E-mail: n.scheltens@vumc.nl.

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Background:Alzheimer’s disease (AD) is a heterogeneous disorder. Objective:To investigate whether cognitive AD subtypes are associated with different rates of disease progression. Methods:We included 1,066 probable AD patients from the Amsterdam Dementia Cohort (n = 290), Alzheimer’s Disease Neuroimaging Initiative (n = 268), Dementia Competence Network (n = 226), and University of California, San Francisco (n = 282) with available follow-up data. Patients were previously clustered into two subtypes based on their neuropsychological test results: one with most prominent memory impairment (n = 663) and one with most prominent non-memory impairment (n = 403). We examined associations between cognitive subtype and disease progression, as measured with repeated Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale sum of boxes (CDR sob), using linear mixed models. Furthermore, we investigated mortality risk associated with subtypes using Cox proportional hazard analyses. Results:Patients were 71±9 years old; 541 (51%) were female. At baseline, pooled non-memory patients had worse MMSE scores (23.1±0.1) and slightly worse CDR sob (4.4±0.1) than memory patients (MMSE 24.0±0.1; p < 0.001; CDR sob 4.1±0.1; p < 0.001). During follow-up, pooled non-memory patients showed steeper annual decline in MMSE (–2.8±0.1) and steeper annual increase in CDR sob (1.8±0.1) than memory patients (MMSE – 1.9±0.1; pinteraction<0.001; CDR sob 1.3±0.1; pinteraction<0.001). Furthermore, the non-memory subtype was associated with an increased risk of mortality compared with the memory subtype at trend level (HR = 1.36, CI = 1.00–1.85, p = 0.05). Conclusions:AD patients with most prominently non-memory impairment show faster disease progression and higher risk of mortality than patients with most prominently memory impairment.

Keywords: Alzheimer’s disease, clustering, cognition, dementia, disease progression, mortality, phenotypes, subtypes

DOI: 10.3233/JAD-171088

Journal: Journal of Alzheimer's Disease, vol. 65, no. 3, pp. 1029-1039, 2018